1. Field of the Invention
This invention relates to the preparation of 1.alpha.-hydroxy-7-dehydrosteroids and new intermediates obtained thereby.
2. Description of the Prior Art
The conventional synthesis of vitamin D.sub.3 involves conversion of cholesterol to 7-dehydrocholesterol and subsequent irradiation of this diene with ultraviolet light to photochemically convert it to pre-vitamin D.sub.3, which is thermally rearranged to cholecalciferol (cis-vitamin D.sub.3).
Recent discoveries have shown that vitamin D.sub.3 is converted to 25-hydroxyvitamin D.sub.3 in the kidney and this product subsequently undergoes 1.alpha.-hydroxylation in the liver to form 1.alpha.,25-dihydroxy-vitamin D.sub.3. This is the most active form of vitamin D.sub.3 that has been found.
Much work has been done in an effort to synthetically prepare the various derivatives of vitamin D.sub.3. Among the procedures developed, most have been concerned with sequentially introducing the desired functional groups into the steroid nucleus, i.e., the 25-hydroxy group, the 1.alpha.-hydroxy group, the 7-ene functionality, etc. Attempts also have been made to introduce the 1.alpha.-hydroxy group and the 7-ene functionality in the same set of reactions. For example, the following two routes have been described. ##STR1##
However, both routes possess serious drawbacks. In Route A, the lithium reduction is not a high yield (55% in the reduction) as also is the case for the allylic bromination-dehydrobromination. See Sato et al, Chem. Pharm. Bull., 2933, 26 (1978) and U.S. Pat. No. 3,993,675, Uskokovic et al, Nov. 23, 1976. In Route B, the deconjugation procedure is quite unreliable and low-yielding. See Ochi et al, J. Chem. Soc. Perkin I, 165 (1979); Kaneko et al, Tetrahedron 30, 2701 (1974) and Guest et al, J. Chem. Soc. Perkin I, 1695 (1979). With the large number of steps needed to complete these sequences, low yields are especially undesirable.
Another method for the generation of the 5,7-diene is by formation of the enol acetate of a .DELTA..sup.4,6 -3-ketone: ##STR2##
However, a serious drawback to this approach is that the 4,6-diene-3-one also enolizes in the other direction forming undesired .DELTA..sup.2,4,6 side product (F') in admixture with the desired .DELTA..sup.3,5,7 product (F). Efforts at directing enolization in the desired direction have met with only partial success. See Dauben et al, J. Amer. Chem. Soc., 73, 4496 (1951) and Zderic et al, Steroids, 1, 233 (1963).
Reference is made to Velluz et al, Bull. Soc. Chem. Fr. 1289 (1957) who disclose yields from enol acetylation of 90% and 83% (Compounds IV and VII respectively). However, these yields are obtained by acylating 19-nor steroids, i.e., steroids having no methyl group attached to the 10 position. Enolization to the .DELTA..sup.3,5,7 triene is highly favored where the 19-methyl group is absent.
In another instance Whalley et al, J. Chem. Soc. Perkin I, 820 (1977), starting with the 7-ene functionality, i.e., with 5.alpha.-cholest-7-en-3.beta.-ol (G), prepared cholesta-1,3,5,7-tetraen-3-yl acetate (I) via oxidation, bromination, dehydrobromination and enol acetylation and from this prepared 1.alpha.-hydroxy-7-dehydrocholesterol (J). ##STR3##
However, application of this procedure to substrates possessing 25-hydroxyl or ester group often leads to by-products due to elimination in the side-chain caused by presence of a strong acid catalyst. Further, the initial substrate, 5.alpha.-cholest-7-en-3.beta.-ol (G) is itself produced by hydrogenation of 7-dehydrocholesterol (Fieser et al, J. Amer. Chem Soc., 75, 121 (1953)) which itself contains the 5,7-diene system and, therefore, is not a practical starting point for a commercially feasible synthesis of the same 5,7-diene system.